Repair of the dura (duraplasty) is indicated following traumatic, neoplastic, or inflammatory destruction, surgical excision, or congenital absence. Dural replacements are used in cranial surgery when primary closure of native dura is not possible. Historically, numerous materials have been used including metal foils, human tissues, animal tissues (porcine dermis, bovine collagen and pericardium) and polymers (PTFE, polyglactin, hydroxyethylmethacrylate). Animal tissues remain the best of the currently available materials with bovine pericardium and bovine collagen being the market leaders (e.g., Duragen®, Duraform®). However, the animal material carries the possibility of infection by prions that may cause mad cow disease. Also, bovine collagen often resorbs within two weeks, prior to complete healing of the dura. Additionally, bovine pericardium is sometimes cross-linked with glutaraldehyde, which has natural biotoxicity. Synthetic materials have handling deficiencies and may cause cerebrospinal fluid (CSF) leakage if not properly sutured in place.
Cellulose of various origins has been proven to be a versatile biomaterial. Synthesized by just about every type of plant and a select number of bacteria, it is a natural, renewable, biocompatible, and biodegradable polymer used in a wide variety of applications.
However, native cellulose cannot be resorbed in human body due to the lack of enzymatic machinery able to break down its highly crystalline structure, which is stabilized by inter and intra hydrogen bonds. Resorbability of cellulose can, however, be achieved through oxidation using various chemicals, including metaperiodate, hypochlorite, dichromate, or nitrogen dioxide (see Stilwell et al., Oxidized cellulose: Chemistry, Processing and Medical Applications, Handbook of Biodegradable Polymers: 1997, 291-306.). Oxidized plant cellulose has been successfully used as a resorbable hemostat (Johnson and Johnson's Surgicel® since 1949 and more recently by Gelita Medical's Gelitacel® since 2006). Products consisting of plant based oxidized cellulose are commonly used as hemostatic agents, wound dressings and anti-adhesion barriers (see U.S. Pat. No. 6,800,753; Stilwell et al., 1997).
Plant cellulose is oxidized most effectively through the use of nitrogen dioxide gas vapor. However, there are toxic effects to be considered from the use of nitrogen dioxide gas; whereas sodium metaperiodate has proven to be more selective when oxidizing highly crystalline celluloses with minimal side reactivity (see Nevell T., Oxidation, Methods in Carbohydrate Chemistry, New York: Academic Press 1963; 3: 164-185). Its oxidizing effects and methods of use have been studied extensively on plant cellulose (see Stilwell et al., 1997; Kim et al., Periodate oxidation of crystalline cellulose, Biomacromolecules 2000; 1: 488-492; Calvini et al., FTIR and WAXS analysis of periodate oxycellulose: Evidence for a cluster mechanism of oxidation, Vibrational Spectroscopy 2006; 40: 177-183.; Singh et al., Biodegradation studies on periodate oxidized cellulose, Biomaterials 1982; 16-20; Devi et al., Biosoluble surgical material from 2,3-dialdehyde cellulose, Biomaterials 1986; 7: 193-196.; Laurence et al., Development of resorbable macroporous cellulosic material used as hemostatic in an osseous environment, J Biomed Mater Res 2005; 73A: 422-429; Roychowdhury and Kumar, Fabrication and evaluation of porous 2,3-dialdehyde cellulose membrane as a potential biodegradable tissue-engineering scaffold, J Biomed Mater Res 2006; 76A: 300-309.). The mechanism of oxidation using periodate relies on cleavage of the C2-C3 bond in the glucopyranose ring and formation of dialdehyde groups. Such a dialdehyde cellulose is believed to degrade by hydrolysis under physiological conditions seen in the body into 2,4-dihydroxybutyric acid and glycolic acid (see Singh et al, 1982). Both of these degradation products are known to be biocompatible and biodegradable and can be metabolized by the body (see Devi et al., 1986; Singh et al., 1982). Once the degradation process is initiated it continues along the glucan chains that comprise the cellulose network (see Stilwell et al., 1997).
Methods for oxidation of bacterially-derived cellulose have also been described in U.S. Pat. No. 7,709,631. Bacterially-derived cellulose possesses unique physical and mechanical properties which results from its three-dimensional structure. Due to its handling characteristics, biocompatibility, and safety, it is already used in several medical devices, for example as described in U.S. Pat. Nos. 7,374,775 and 7,510,725. One type of microbial cellulose synthesized by Acetobacter xylinum (reclassified as Gluconacetobacter xylinus) is characterized by a highly crystalline three-dimensional network consisting of pure cellulose nanofibers. Microbial cellulose has long been recognized as a biomaterial with potential applications for temporary wound coverage, for treatment of chronic wounds and burns, and as a scaffold for tissue growth, synthetic blood vessels, as well as many other biomedical applications (Fontana et al., Acetobacter cellulose pellicle as a temporary skin substitute, Appl Biochem Biotechnol 1990; 24/25: 253-264; Alvarez et al, Effectiveness of a Biocellulose Wound Dressing for the Treatment of Chronic Venous Leg Ulcers: Results of a Single Center Random, Wounds 2004; 16: 224-233; Czaja et al., The future prospects of microbial cellulose in biomedical applications, Biomacromolecules 2007; 8(1): 1-12; Klemm et al., Cellulose: Fascinating Biopolymer and Sustainable Raw Material, Angew Chem, Int Ed 2005; 44: 3358-3393; Bodin et al., Bacterial cellulose as a potential meniscus implant, J Tissue Eng and Regen Med 2007; 1(5): 406-408; Svensson et al., Bacterial cellulose as a potential scaffold for tissue engineering of cartilage, Biomaterials 2005; 26 (4): 419-431).
Although methods for oxidizing cellulose are widely described in the literature they often do not result in homogenously oxidized materials with the most desirable properties for medical applications. It is particularly true for soft tissue applications, for example dural repair applications, where the material needs to be able to rehydrate, readily conform to the various contours of the body, have adequate strength to allow easy handling, but also to be resorbable over a time frame that is compatible with healing of the particular anatomical site. Consequently there is a need for oxidized cellulose biomaterials and methods for producing the same that can achieve these desired properties.
The ideal material should be able to prevent CSF leakage, have good biocompatibility, be free of potential risk of infection, have good intra-operative handling, have mechanical properties similar to dura, have a resorption profile beneficial to tissue regrowth, and be readily available and storable.